PD-1 inhibitors versus chemotherapy as second-line treatment for advanced esophageal squamous cell carcinoma: a meta-analysis

Abstract Background Aim to establish the inhibitors of programmed cell death protein 1 (PD-1) as second-line therapy for advanced esophageal squamous cell carcinoma (ESCC). Methods Published clinical trials in the PubMed, Medline, Embase databases on PD-1 inhibitors for the treatment of ESCC were searched, along with an additional search on abstracts from the American Society of Clinical Oncology (ASCO) and European Society for Medical Oncology (ESMO) from inception to September 2021. Overall survival (OS), progression-free survival (PFS), objective response rate (ORR), disease control rate (DCR), and treatment-related adverse events (TRAEs) were synthesized using STATA. Results A total of 1970 patients (PD-1 inhibitors: 987; chemotherapy: 983) were enrolled in five randomized controlled trials. Compared with conventional chemotherapy, second-line PD-1 inhibitors significantly improved the OS (hazard ratio [HR] = 0.73, 95% confidence interval [CI]: 0.66–0.81; P < 0.001) and ORR (relative risk [RR] = 1.89, 95% CI: 1.16–3.05; P = 0.01) of advanced ESCC patients, especially significantly prolonged the OS in the patients with positive programmed death-ligand 1 (PD-L1) status (HR = 0.64, 95% CI: 0.53–0.77; P < 0.001); but did not better PFS (HR = 0.88, 95% CI: 0.68–1.14; P = 0.330) and DCR (RR = 0.89, 95% CI: 0.59–1.37; P = 0.603). Moreover, PD-1 inhibitors were associated with statistically lower incidences of grade 3–5 TRAEs. Conclusion Second line PD-1 inhibitors significantly improved the OS and ORR of patients with advanced ESCC, especially the OS of those with positive PD-L1 expression, and did not result in significant improvement in PFS and DCR. Compared to chemotherapy, second-line PD-1 inhibitors had superior safety profiles for the treatment of advanced ESCC.

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Retrospective study of nivolumab monotherapy for advanced esophageal squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.179 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 179-179

Author(s):

Hayato Mikuni ◽

Shun Yamamoto ◽

Kotoe Oshima ◽

Hidekazu Hirano ◽

Natsuko Okita ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Objective Response ◽

Progression Free Survival ◽

Line Treatment ◽

Second Line ◽

Treatment Rate ◽

Practice Methods

179 Background: Based on the results of the ATTRACTION-1 and ATTRACTION-3 trials, nivolumab monotherapy has used for the treatment of metastatic or recurrence esophageal cancer patients who were refractory or intolerant to fluoropyrimidine and platinum since February 2020 in Japan. However, the ATTRACTION-1 trial mainly included patients who received nivolumab monotherapy as third or later-line treatments, which was different from the ATTRACTION-3 trial which mainly included patients as second-line treatment. Therefore, it is still unclear whether the treatment lines affect the efficacy of nivolumab in clinical practice. Methods: Medical records were retrospectively reviewed for patients diagnosed with metastatic or recurrence esophageal squamous cell carcinoma (ESCC) who received nivolumab monotherapy as second- or third or later-line treatments in our hospital. We evaluated progression-free survival (PFS), overall survival (OS), objective response rate (ORR), disease control rate (DCR) based on the RECIST ver1.1, and the incidences of adverse events (AEs) based on the CTCAE ver5.0. Results: Sixty-two patients were identified as the subject of this study. Thirty patients received nivolumab as second-line treatment (48.4%) and 32 patients as third or later-line treatments (51.6%). The median age (range) were 67 (33-80)/61 (52-84), PS 0 were 40.0/21.9%, prior taxane treatment rate were 6.7/93.8%, respectively. The ORR/DCR were 22.7/45.5% in second-line treatment, and 24.1/44.8% in third or later-line treatments (p=1.00). The median PFS (95% CI) was 2.3 (1.4-6.2)/2.3 (1.2-3.6) months in the second-/third or later-line treatments (HR=0.86, p=0.58). AEs of grade 3 or higher were observed in 6.7/6.3% of the second-/third or later-line treatments. Conclusions: There was no clear difference between second -line and third or later-line treatments in the short-term efficacy of nivolumab monotherapy in advanced ESCC patients.

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659 AN SINGLE-ARM OPEN-LABEL PHASE II STUDY OF CAMRELIZUMAB PLUS APATINIB AS SECOND-LINE TREATMENT FOR ADVANCED ESOPHAGEAL SQUAMOUS CELL CARCINOMA

Diseases of the Esophagus ◽

10.1093/dote/doab052.659 ◽

2021 ◽

Vol 34 (Supplement_1) ◽

Author(s):

Feng Wang ◽

Qingxia Fan ◽

Junsheng Wang ◽

Tao Wu ◽

Yonggui Hong ◽

...

Keyword(s):

Overall Survival ◽

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Phase Ii ◽

Squamous Cell ◽

Objective Response ◽

Phase Iii ◽

Line Treatment ◽

Second Line

Abstract Esophageal squamous cell carcinoma (ESCC) as a common malignancy is prevalent in East Asia and in eastern and southern Africa. Although pembrolizumab, nivolumab and camrelizumab are respectively recommended as second-line treatment for advanced ESCC due to improved overall survival (OS), objective response rate (ORR) was modest. New effective treatments are needed. Hence, the study of camrelizumab plus apatinib (VEGFR2 inhibitor) as second-line treatment for advanced ESCC was performed. Methods This ongoing phase II trial (NCT03736863) in six sites in China enrolled pts aged 18-75 with unresectable locally advanced, locally recurrent, or metastatic ESCC that progressed or were intolerant after first-line chemotherapy, and an ECOG performance status of 0-1. Pts received 200 mg camrelizumab intravenously every 2 weeks and apatinib 250 mg orally once per day in 4-week cycles until disease progression, unacceptable adverse events (AEs) or withdrawal of consent. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and OS. Results At data cutoff (Feb 28, 2021), 52 pts were enrolled, including 42 males and 50 with distant metastases, with the median age of 62 years. In the evaluable population of 39 pts, ORR without confirmation was 43.59% and DCR was 94.87%. The median duration of response was 6.9 months (95% CI 4.57–9.23). The median PFS was 6.8 month (95% CI 2.66–10.94). The 12-month overall survival was 52.2%. A total of 80.8% of pts had treatment-related AEs (TRAEs) with 46.2% of grade ≥ 3 TRAEs. The safety profile of camrelizumab and apatinib was consistent with other anti–PD-1 antibodies and angiogenesis inhibitors. Conclusion This is the first study that evaluates the combination anti–PD-1 antibody and anti-angiogenesis inhibitor as a second-line therapy for advanced ESCC. Camrelizumab plus apatinib showed encouraging clinical efficacy and acceptable safety. Further phase III randomized trials are warranted.

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Safety results of a phase III randomized trial of comparison of three paclitaxel-based regimens concurrent with radiotherapy for patients with local advanced esophageal squamous cell carcinoma (ESO-Shanghai 2).

Journal of Clinical Oncology ◽

10.1200/jco.2019.37.15_suppl.4055 ◽

2019 ◽

Vol 37 (15_suppl) ◽

pp. 4055-4055

Author(s):

Dashan Ai ◽

Yun Chen ◽

Qi Liu ◽

Xiangpeng Zheng ◽

Yunhai Li ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Adverse Events ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Clinical Stage ◽

Progression Free Survival ◽

Phase Iii ◽

Consolidation Chemotherapy ◽

Grade 3

4055 Background: Paclitaxel (PTX) is effective in concurrent chemoradiation (CCR) against esophageal squamous cell carcinoma (ESCC) . Which regimen, among cisplatin (DDP) (TP), carboplatin (CBP) (TC) or 5-Fu (TF) in combination with PTX concurrent with radiotherapy, provides best prognosis with minimum adverse events (AEs) is still unknown. Methods: The study compared two pairs of regimens: TF vs. TP and TF vs. TC concurrent with radiotherapy. Patients with histologically confirmed ESCC (clinical stage II, III or IVa) were randomized into the three groups. Patients in TP group were treated with 2 cycles of CCR followed by 2 cycles of consolidation chemotherapy with TP (DDP 25 mg/m2/d, d1-3, PTX 175 mg/m2, d1, q28d). Patients in TF group were treated with 6 cycles of TF (5-Fu 300 mg/m2, civ 96h, PTX 50 mg/m2, d1, qw) in CCR followed by 2 cycles of TF (5-FU 1800 mg/m2, civ 72h, PTX 175 mg/m2, d1, q28d) in consolidation chemotherapy. Patients in TC group were treated with 6 cycles of TC (CBP AUC = 2, d1, PTX 50 mg/m2, d1, qw) in CCR followed by 2 cycles of TC (CBP AUC = 5, d1, PTX 175 mg/m2 d1, q28d) in consolidation chemotherapy. The radiotherapy dose in all groups was 61.2 Gy delivered in 34 fractions. The primary endpoint was overall survival and the secondary endpoints were progression-free survival and adverse events. Results: Between July 2015 and January 2018, 321 ESCC patients in 11 centers were enrolled. TP group had a significant higher incidence of acute grade 3/4 neutropenia (59.7% vs. 16.8%(TF) or 32.4%(TC)), thrombocytopenia (12.7% vs. 3.5%(TF) or 6.2%(TC)), anemia (6.4% vs. 4.4%(TF) or 4.4%(TC)), fatigue (10.0% vs. 0.9%(TF) or 0.9%(TC)) and vomiting (5.5% vs. 0%(TF) or 0.9%(TC)) than other two groups ( P < 0.05). TF group had a significant higher incidence of grade 3/4/5 esophagitis (13.1% vs. 1.8%(TP) or 5.3%(TC)) and pneumonitis (4.4% vs. 0%(TP) or 1.8%(TC)) than other two groups ( P < 0.05). One patient in TF group died of acute pneumonitis. One patient in TF group and one in TC group died of acute esophagitis. Conclusions: TP and TF regimen showed different severe AEs in CCR in ESCC patients and TC showed mild AEs. Clinical trial information: NCT02459457.

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Clinical and biomarker analyses of sintilimab versus chemotherapy as second-line therapy for advanced or metastatic esophageal squamous cell carcinoma: a randomized, open-label phase 2 trial (ORIENT-2)

10.21203/rs.3.rs-469826/v1 ◽

2021 ◽

Author(s):

Jian Ming Xu ◽

Yi Li ◽

Qingxia Fan ◽

Yongqian Shu ◽

Lei Yang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Objective Response ◽

Progression Free Survival ◽

Phase 2 ◽

Open Label ◽

Phase 2 Trial ◽

Open Label Phase

Abstract This randomized, open-label, multi-center phase 2 study (ClinicalTrials.gov, number NCT03116152) assessed sintilimab, a PD-1 inhibitor, versus chemo in patients with advanced esophageal squamous cell carcinoma (ESCC) refractory to first-line (1L) chemotherapy. The primary endpoint was overall survival (OS), while exploratory endpoint was the association of biomarkers with treatment efficacy. The median OS in the sintilimab group was significantly prolonged compared with that of the chemotherapy group, (objective response rates 12.6% and 6.3 %, respectively). Incidence of treatment-related adverse events of grade 3–5 was lower with sintilimab than with chemotherapy (20.2 vs. 39.1 %). Patients with high TCR clonality and low mTBI showed the longest median OS (15.0 mo), while patients with low NLR at 6 wk post-treatment had a significantly prolonged median OS compared with those with high NLR. High expression of T-follicular helper cells or activated B-cell signature was significantly associated with longer progression-free survival in the sintilimab group.

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Outcomes of Definitive Chemoradiotherapy for Stage IVa (T4b vs. N4) Esophageal Squamous Cell Carcinoma Based on the Japanese Classification System: A Retrospective Single-Center Study

Cancers ◽

10.3390/cancers13010008 ◽

2020 ◽

Vol 13 (1) ◽

pp. 8

Author(s):

Yuki Wada ◽

Akira Anbai ◽

Noriko Takagi ◽

Satoshi Kumagai ◽

Eriko Okuyama ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Objective Response ◽

Progression Free Survival ◽

Japanese Classification ◽

System A ◽

Single Center Study ◽

Progression Patterns

The differences in prognoses or progression patterns between T4b non-N4 and non-T4b N4 esophageal squamous cell carcinoma post chemoradiotherapy (CRT) is unclear. This study compared the outcomes of CRT for stage IVa esophageal squamous cell carcinoma according to T/N factors. We retrospectively identified 66 patients with stage IVa esophageal squamous cell carcinoma who underwent definitive CRT at our center between January 2009 and March 2013. The treatment outcomes, i.e., progression patterns, prognostic factors, and toxicities based on version 5.0 of the National Cancer Institute Common Terminology Criteria for Adverse Events, were studied. The patients (56 men and 10 women) had a median age of 67 (range: 37–87) years. The T/N classifications were T4b non-N4 (28/66), non-T4b N4 (24/66), and T4b N4 (14/66). Objective response was achieved in 57 patients (86.4%, (95% confidence interval, 74.6–94.1%)). There were no significant differences between the T/N groups in terms of overall survival, progression-free survival, and progression pattern. We found no significant differences in prognoses or progression patterns among patients with T4b non-N4, non-T4b N4, and T4b N4 esophageal squamous cell carcinoma. Thus, it seems impractical to modify CRT regimens based on T/N factors.

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Comparison of PD-1 Inhibitors in Patients With Advanced Esophageal Squamous Cell Carcinoma in the Second-Line Setting

Frontiers in Oncology ◽

10.3389/fonc.2021.698732 ◽

2021 ◽

Vol 11 ◽

Author(s):

Yi-Xin Zhou ◽

Ping Chen ◽

Yu-Ting Sun ◽

Bei Zhang ◽

Miao-Zhen Qiu

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Survival Benefit ◽

Objective Response ◽

Indirect Comparison ◽

Squamous Carcinoma ◽

Second Line ◽

Line Setting

BackgroundKEYNOTE-181, ATTRACTION-3, and ESCORT trials have opened the era of programmed death 1 (PD-1) inhibitors in the second-line therapy for esophageal squamous cell carcinoma (ESCC). There is no head-to-head comparison of pembrolizumab vs. nivolumab vs. camrelizumab in the second-line setting for ESCC. We performed an indirect comparison to explore the optimal choice of immune checkpoint inhibitor (ICI) for advanced ESCC.MethodsPatients in ATTRACTION-3 and ESCORT were all squamous carcinoma, while KEYNOTE-181 enrolled both adenocarcinoma and squamous carcinoma patients. We only extract information of patients with squamous carcinoma from KEYNOTE 181 study and all the patients from ATTRACTION-3 and ESCORT. The main clinical outcomes for this study were overall survival (OS), progression-free survival (PFS), objective response rate (ORR), and treatment-related adverse events (TRAEs).ResultsIndirect analysis showed similar survival benefit among three PD-1 inhibitors. Nivolumab was comparable with pembrolizumab in most subgroups except that nivolumab was slightly better for patients with performance status (PS) score of 1 [HRnivo/pembro: 0.68 (95% confidence interval (CI): 0.45–1.02], p = 0.07). Compared with nivolumab indirectly, pembrolizumab and camrelizumab had better PFS [HRpembro/nivo: 0.85 (95% CI: 0.63–1.14), p = 0.29; HRcam/nivo: 0.64 (95% CI: 0.47–0.87), p = 0.004] and significantly higher ORR [RRpembro/nivo: 2.51 (95% CI: 1.22–5.15), p = 0.01; RRcam/nivo: 3.52 (95% CI: 1.73–7.18), p = 0.001]. Compared with camrelizumab indirectly, pembrolizumab had slightly worse PFS [HRpembro/cam: 1.33 (95% CI: 0.99–1.79), p = 0.057] and comparable ORR [RRpembro/cam: 0.71 (95% CI: 0.32–1.60; p = 0.41)]. Camrelizumab had a significantly higher rate of all grade TRAEs than both pembrolizumab and nivolumab.ConclusionsCombining the safety and potential survival benefit, we recommend nivolumab for ESCC patients with PS score of 1 and pembrolizumab or camrelizumab for patients with better PS and seeking for higher efficacy or longer PFS.

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A prospective, nonrandomized phase II/III trial of definitive chemoradiation, with or without cetuximab, in advanced esophageal squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2012.30.15_suppl.e14645 ◽

2012 ◽

Vol 30 (15_suppl) ◽

pp. e14645-e14645

Author(s):

Yongshun Chen ◽

Jianhua Wang ◽

Xiaoyuan Wu ◽

Chunyu He ◽

Wen Wang ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Objective Response ◽

Progression Free Survival ◽

Chinese Patients ◽

Free Survival ◽

Group A ◽

Group B

e14645 Background: Chemoradiotherapy is the standard treatment option for patients with esophageal cancer unsuitable for surgery, but the majority of patients will die of their disease, most commonly with local tumor progression/recurrence. We initiated this study to determine the efficacy and safety of the addition of cetuximab with paclitaxel, cisplatin, and radiation for patients with advanced esophageal squamous cell carcinoma (ESCC). Methods: A total of 127 patients with clinical stage II–IVa disease were selected to receive combined-modality therapy consisting of cetuximab (400 mg/m2/wk week 1, then 250 mg/m2/wk week 2-8), paclitaxel (45 mg/m2/wk) and cisplatin (20 mg/m2/wk) in weeks 2-8 with 59.4 Gy of radiation (Group A, n = 29) versus the same chemoradiotherapy schedule but without cetuximab (Group B, n = 98). Results: At the time of this analysis, 27 and 88 patients were available for evaluation of response and survival in Group A and B respectively. In Group A, 20 patients (74.1%) achieved complete response (CR) and 7 (25.9%) achieved partial response (PR), resulting in an objective response rate (ORR) of 100%. The 1- and 2-year progression-free survival (PFS) was 91.2% and 85.1%, the median PFS was not reached. No association between tumor EGFR expression and response or survival was found. In Group B, 33 patients (37.5%) achieved CR, 51 (58.0%) achieved PR and 4 (4.5%) had stable disease, thus the ORR was 95.5%. The 1- and 2-year PFS was 89.0% and 50.5%, with the median PFS of 24.3 months. The difference in PFS between the two groups was statistically significant (p = 0.011). Treatment-related toxicities were generally grade 1 or 2. The most common toxicities were rash (89.3%), followed by neutropenia (71.4%) and esophagitis (60.7%) in chemoradiation-plus-cetuximab group. Adverse events were most often neutropenia (81.8%) and esophagitis (76.1%) in chemoradiation group. Locoregional failure rate was 3.7% and 15.9% in Group A and B, respectively. Conclusions: Cetuximab can be safely administered with chemoradiation and may prolong progression-free survival for Chinese patients with ESCC.

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Final results of a phase III randomized trial of comparison of three paclitaxel-based regimens concurrent with radiotherapy for patients with local advanced esophageal squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2020.38.15_suppl.4564 ◽

2020 ◽

Vol 38 (15_suppl) ◽

pp. 4564-4564

Author(s):

Dashan Ai ◽

Jinjun Ye ◽

Yun Chen ◽

Qi Liu ◽

Xiangpeng Zheng ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Adverse Events ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Squamous Cell ◽

Clinical Stage ◽

Progression Free Survival ◽

Phase Iii ◽

Consolidation Chemotherapy ◽

Grade 3

4564 Background: Paclitaxel (PTX) is effective in concurrent chemoradiation (CCR) against esophageal squamous cell carcinoma (ESCC). Which regimen, among cisplatin (DDP) (TP), carboplatin (CBP) (TC) or 5-Fu (TF) in combination with PTX concurrent with radiotherapy, provides best prognosis with minimum adverse events (AEs) is still unknown. Methods: The study compared two pairs of regimens: TF vs. TP and TF vs. TC concurrent with radiotherapy. Patients with histologically confirmed ESCC (clinical stage II, III or IVa) 20 were randomized into the three groups. Patients in TP group were treated with 2 cycles of CCR followed by 2 cycles of consolidation chemotherapy with TP (DDP 25 mg/m2/d, d1-3, PTX 175 mg/m2, d1, q28d). Patients in TF group were treated with 6 cycles of TF (5-Fu 300 mg/m2, civ 96h, PTX 50 mg/m2, d1, qw) in CCR followed by 2 cycles of TF (5-FU 1800 mg/m2, civ 72h, PTX 175 mg/m2, d1, q28d) in consolidation chemotherapy. Patients in TC group were treated with 6 cycles of TC (CBP AUC = 2, d1, PTX 50 mg/m2, d1, qw) in CCR followed by 2 cycles of TC (CBP AUC = 5, d1, PTX 175 mg/m2 d1, q28d) in consolidation chemotherapy. The radiotherapy dose in all groups was 61.2 Gy delivered in 34 fractions. The primary endpoint was overall survival (OS) and the secondary endpoints were progression-free survival (PFS) and adverse events. Results: Between July 2015 and January 2018, 321 ESCC patients in 11 centers were enrolled. Median follow-up of patients who survived was 36.3 months (IQR 27.9–45.2). The 3-yr OS was 58.2% in TF group and 59.5% in both TP and TC group. (TF vs. TP, HR 0.935, 95% CI 0.627-1.417; TF vs. TC, HR 0.881, 95% CI 0.578-1.342; P = 0.839). No significant differences were found in 3-yr PFS between TF, TP and TC groups [48.3% vs. 45.5%(TP) or 48.3% (TC). P = 0.820]. TP group had a significant higher incidence of acute Grade 3/4 neutropenia [60.7% vs. 16.8%(TF) or 32.7%(TC)], thrombocytopenia [13.1% vs. 2.8%(TF) or 4.7%(TC)], anemia [5.6% vs. 1.9%(TF) or 3.7% (TC)], fatigue [10.3% vs. 1.9%(TF) or 0.9%(TC)] and vomiting [5.6% vs. 0%(TF) or 0.9%(TC))]than other two groups ( P< 0.05). TF group had a significant higher incidence of Grade 3/4/5 esophagitis [11.2% vs. 0.9%(TP) or 4.7%(TC))]and pneumonitis [4.6% vs. 0%(TP) or 1.9% (TC)]than other two groups ( P< 0.05). Conclusions: No statistical differences were found in OS and PFS among TF, TP and TC groups. TC might be an option used in CCR in ESCC patients with mild of side effects compared with other two groups, although it did not significantly prolong OS. Clinical trial information: NCT02459457 .

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The preliminary efficacy and safety of KN046 plus concurrent chemoradiation therapy in recurrent and metastatic esophageal squamous cell carcinoma.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.223 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 223-223

Author(s):

Bing Song Qin ◽

Qi Zhao ◽

Dong Yan Liu ◽

Jiao Xue ◽

Xing Jia Zhu

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Disease Control ◽

Cell Carcinoma ◽

Squamous Cell ◽

Objective Response ◽

Chemoradiation Therapy ◽

Disease Control Rate ◽

Concurrent Chemoradiation ◽

Grade 3

223 Background: Definitive or palliative chemoradiation therapy has been employed in the management of esophageal squamous cell carcinoma (ESCC). Immune checkpoint inhibitor has improved outcomes in metastatic stage IV pts. Here we report the addition of KN046, a PD-L1/CTLA-4 bispecific antibody, to concurrent chemoradiation (CRT) therapy to determine the safety and efficacy of this approach (ChiCTR2000031544). Methods: Pts with recurrent or metastatic ESCC, not been treated by CRT or other systemic treatment within 6 months, were recruited and received palliative CRT consisting of cisplatin (75 mg/m2 IV Q3W for 4~6 cycles), paclitaxel (135~175 mg/m2 IV Q3W for 4-6 cycles) and radiation (SBRT or conventional and dose are determined at the investigator’s discretion according to institutional standard). KN046 at ascending doses of 1, 3 and 5 mg/kg Q3W was added within 7-14 days after the completion of radiation therapy (RT) and concurrently with chemotherapy, followed by KN046 Q2W maintenance. Dose limiting toxicities (DLTs) were assessed for the first treatment cycle of KN046. Anti-tumor activity was assessed according to RECIST 1.1 every 6 weeks within the first year, and every 12 weeks thereafter. Results: As of June 30, 2020, 18 subjects were enrolled and received KN046 treatment (1mg/kg, n = 3; 3mg/kg, n = 11; 5mg/kg, n = 4). The median KN046 exposure was 11.5 weeks. No DLT was reported. 3 (16.7%) subjects experienced Grade 3, KN046 related adverse events (1 Grade 3 pneumonitis and 2 Grade 3 colitis recovered after steroid and antibiotic Tx). For 18 evaluable subjects, the disease control rate and objective response rate were 94.4% and 44.4%, respectively. DOR and PFS were not matured yet as of cutoff date. At 3 mg/kg, objective response was observed in 5 out of 9 subjects (55.6%) with measurable disease and disease control rate was 100%; 7/9 (77.8%) subjects experienced further tumor reduction after initiation of KN046 treatment. It is worth to note that, 2 subjects at 3mg/kg achieved complete response after receiving KN046 treatment. Conclusions: The addition of KN046 to CRT was well tolerated and showed promising efficacy signal in recurrent or metastatic ESCC. This pilot study enables further investigation of a new treatment modality of KN046 with CRT in this detrimental disease with poor prognosis. Clinical trial information: 2000031544.

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Camrelizumab in combination with apatinib as second-line treatment for advanced esophageal squamous cell carcinoma: A single-arm, open-label, phase II study.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.3_suppl.215 ◽

2021 ◽

Vol 39 (3_suppl) ◽

pp. 215-215

Author(s):

Feng Wang ◽

Junsheng Wang ◽

Tao Wu ◽

Yonggui Hong ◽

Xiangrui Meng ◽

...

Keyword(s):

Squamous Cell Carcinoma ◽

Esophageal Squamous Cell Carcinoma ◽

Cell Carcinoma ◽

Phase Ii ◽

Squamous Cell ◽

Phase Iii ◽

Line Treatment ◽

Second Line ◽

Grade 3

215 Background: Esophageal squamous cell carcinoma (ESCC) is a lethal cancer with a high unmet medical need. Camrelizumab, an anti-PD-1 monoclonal antibody, significantly improved overall survival (OS) and objective response rate (ORR) in Chinese patients (pts) with advanced ESCC compared with chemotherapy, with a manageable safety profile in phase III randomized trial (ESCORT). However, the absolute long-term survival benefiting from PD-1 inhibitors is limited, and new effective treatments are needed. Here, our study aimed to assess the efficacy and safety of combination with camrelizumab and apatinib (VEGFR2 inhibitor) as second-line treatment for advanced ESCC. Methods: This ongoing phase II trial (NCT03736863) in six sites in China enrolled pts aged 18-75 with unresectable locally advanced, locally recurrent, or metastatic ESCC that progressed or were intolerant after first-line chemotherapy, and an ECOG performance status of 0-1. Pts received 200 mg intravenous camrelizumab every two weeks plus 250 mg oral apatinib daily in 4-week cycles until disease progression, unacceptable adverse events (AEs) or withdrawal of consent. The primary endpoint was investigator-assessed ORR. Secondary endpoints included disease control rate (DCR), progression-free survival (PFS) and OS. Results: At data cutoff (Sept 11, 2020), 36 pts were enrolled, 7 females and 29 males, and 25 pts had lymph node metastases. Twelve pts received radiotherapy and 25 underwent surgery. Twenty-five pts were included in the efficacy analysis with median follow-up time of 5.0 months and 36 pts in the safety analysis with median follow-up time of 4.6 months. The primary endpoint ORR without confirmation was 40 % with complete response in two pts (8%) and partial response in eight pts (32%). Thirteen pts (52%) had stable disease, and the DCR was 92%. The median PFS and OS were not reached. A total of 72.2% of pts had AEs, and 30.6% of pts experienced grade 3 AEs. The most common AEs (all grade, grade≥3) were elevated aspartate aminotransferase (30.6%, 19.4%), elevated alanine aminotransferase (30.6%, 13.9%), hypertension (25%, 2.8%),neutrophil (25%, 5.6%), thrombocytopenia (25%, 0%), leukopenia (22.2%, 2.8%), anemia (11.1%, 0%), proteinuria (11.1%, 0%), hematochezia (8.3%, 0%), reactive cutaneous capillary endothelial proliferation (5.6%, 2.8%), pruritus (5.6%, 0%), esophageal fistula (5.6%, 0%), fatigue (2.8%, 0%) and hypothyroidism (2.8%, 0%). Conclusions: This is the first study to explore the combination of PD-1 inhibitor and anti-angiogenesis inhibitor as a second-line treatment for advanced ESCC. Camrelizumab plus apatinib demonstrated encouraging clinical efficacy and acceptable safety as second-line treatment, and might be a favorable option for pts with advanced ESCC. Further phase III randomized trials are warranted. Clinical trial information: NCT03736863.

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